Synthesis of vincamine



United States Patent 3,454,583 SYNTHESIS OF VIN CAMINE Martin E. Kuehne,Burlington, Vt., assignor to the United States of America as representedby the Secretary of the Department of Health, Education, and Welfare NoDrawing. Filed July 19, 1965, Ser. No. 475,911 Int. Cl. C07d 57/02,29/22 US. Cl. 260-294.3 1 Claim ABSTRACT OF THE DISCLOSURE Vincamine istotally synthesized from tryptamine and 4-ethyl-4-formyldimethylpimelate, reaction of the resulting lactam ester with phosphoruspentasulfide, desulfurization of the resulting thiolactam ester,oxidation of the resulting aininoester and acid treatment of theoxidized product to yield dl-vincamine. Novel intermediates and epimersare disclosed.

This invention relates to a process for the preparation of vincamine andto the intermediates produced in the process.

Vincamine, the major alkaloid occurring in Vinca minor L,(Apocyanaceae), possesses valuable antihypentensive and sedativeproperties as reported by L. Szporny and K. Szasz, Arch. Exptl. Pathol.Pharmak., 236, 296 (1959). An object of this invention is a new processfor the preparation of pure vincamine by a total synthesis which does norequire the use of costly natural products as starting compounds.

Another object of the invention is the preparation of vincamine fromtryptamine by the scheme and process set forth herein.

A further object of the invention is the obtention of the intermediatesinvolved in the synthesis of vincamine as set forth herein. 7

The steps involved in the synthesis of vincamine (I) and the variousintermediates are set forth in the following III The synthesis firstinvolves the condensation of tryptamine (II) with4-ethyl-4-formyldimethyl pimelate (III), yielding a mixture ofintermediate lactam ester IVa, its epimer IV!) and intermediate lactamacids Va and Vb. The pimelic acid ester (III) is readily obtainable byexhaustive alkylation of the pyrrodiline enamine of butyraldehyde Wmethyl methacrylate, followed by hydrolysis, as reported in J. Org.Chem., 29, 1582 (1964). Hydrolysis of the lactam esters IVa and IV];with aqueous sodium bicarbonate yields the lactam acids Va and Vb, whichare convertible back to the methyl esters Wu and IV!) by reaction withdiazomethane.

Reaction of the esters IVa and N11 with phosphorus pentasulfide yieldsthiolactam esters VIa and VIb. Desulfurization of the thiolactam estersVIa and VII) with Raney nickel yields amino esters VIIa and VIII), whichcan be separated by column chromatography on neutral alumina.

Oxidation of the more rapidly eluted ester VIIa withp-nitrosodimethylaniline and sodium triphenylmethyl, followed by acidtreatment yields dl-vincamine I and epivincamine, the hydroxyepimerthereof. Analogous oxidation of amino ester VIlb yields isovincamine,having D-E ring junction trans and epiisovincamine with DE ring junctiontrans and the hydroxyl group in epimeric orientation.

Oxidation of the animoesters VIIa and VIIb with mercuric acetate yieldsthe didehydroimmonium salt VIII which can be reduced with sodiumborohydride to yield a mixture of the aminoesters VIIa and VIIb.

EXAMPLE The detailed process steps are set forth as follows: A.Dimethyl- (4-ethyl-4-formyl -pirnelate 1-pyrrolidinobutene.A mixture of71 g. (1 mole) of pyrrolidine and 71 g. of anhydrous potassium carbonatewas stirred under an atmosphere of nitrogen. With cooling ein an icebath, 36 g. (0.50 mole) of freshly distilled n-butyraldehyde was addeddropwise. After 1 5 hours at room temperature the liquid was separatedfrom the solid by centrifugation and then distilled at 70 mm. At a bathtemperature of pyrrolidine (0.5 mole) was removed by pyrolysis and theproduct then collected at 8895, giving 31 g. of (0.25 mole) of product.

Dimethyl-(4-ethyl-4-formyl)-pimelates.At 0-5 22. g. (0.18 mole) ofl-pyrrolidinobutene was added dropwise toa stirred solution of 38 g.(0.44 mole) of methylacrylate in ml. of methanol, with stirring under anitrogen atmosphere. After 14 hours at 25 and 36 hours at reflux, 11 ml.of acetic acid in 60 ml. of water was added and refluxing continued foreight hours. The reaction mixture was then concentrated under vacuum,diluted with 300 ml. of water and extracted five times with 100 ml. ofdichloromethane. The extracts were washed with sodium carbonatesolution, dried over magnesium sulfate and concentrated under vacuum.The residual oil was distilled and 20.0 g. (0.082 mole) of the productcollected at 106107 (0.07 mm.).

Analysis.-Calcd. for C H O C, 59.00; H, 8.25. Found: C, 58.88; H, 8.20.

B. 1,2,3,4,6,7,l2, e-octahydro-l-ethyl 1carbomethoxyethyl-4-oxo-indolo-[2,3-a]-quinolizine A solution of 2.4 g.(0.015 mole) of tryptamine and 3.7 g. (0.015 mole) ofdimethyl-4-ethyl-4-formylpimelate in 25 ml. of dry acetic acid wasrefluxed for 20 hours. The solvent was removed under vacuum, 100 ml. ofwater containing 2.0 g. of sodium hydroxide added and the mixtureextracted five times with 100 ml. of dichloromethane. Concentration andcrystallization from ethyl acetate gave 3.8 g. (0.011 mole) of a mixtureof crystalline epimers, M.P. l60-l82.

Analysis.-Calcd. for C H N O C, 71.17; H, 7.39; N, 7.90. Found: C,70.89; H, 7.46; N, 7.59.

Acidification of the basic solution, extraction with dichloromethane,concentration and crystallization from ethanol gave 0.75 g. (0.0020mole) of the corresponding epimeric acids, M.P. 226-240.

Analysis.Calcd. for C H N O C, 70.57; H, 7.11; N, 8.23. Found: C, 70.56;H, 7.12; N, 8.16.

The ratio of acids to esters was variable, increasing with reactiontime. Quantitative conversion of the acids to the methyl esters wasreadily achieved by treatment of a dichloromethane solution of the acidswith an excess of ethereal diazomethane, followed by concentration andcrystallization from ethylacetate.

Conversely, the esters could be saponified by refluxing for 18 hourswith an excess of sodium carbonate in aqueous ethanol.

Alternatively, combination of tryptamine and the above aldehyde inacetic acid at 25 for 3 days produced the corresponding Schifis basediester which could be cyclized to the above lactam esters by heating at180.

C. 1,2,3,4,6,7,12e-octahydro-l-ethyl-l-carbomethoxyindolo(2,3-a)-quinolizine A mixture of1.5 g. (0.00442 mole) of the above lactam ester, 0.93 g. (0.0042 mole)of phosphorous pentasulfide and 15 ml. of 1,2-dimethoxyethane wasstirred at 25 for 6 hours, 2 ml. of dry pyridine added, stirringcontinued for 10 minutes and the mixture then concentrated under vacuum.The residue was treated with 50 ml. of water and 5 ml. of saturatedsodium carbonate solution and extracted six times with 50 ml. portionsof dichloromethane. The combined extracts were concentrated under vacuumand the residue crystallized by addition of a mixture of a mixture ofether and petroleum ether (B.P. 30-60"). Recrystallization from ethylacetate and petroleum ether (B.P. 30-60) gave 0.90 g. (0.0024 mole) ofthe epimeric thioamides, M.P. 130-137. The mixture of epimers could beseparated by chromatography on 50 g. of neutral, activity II aluminawith benzene as eluant. The more rapidly eluted epimer had a M.P.163-164 and the less rapidly eluted epimer a M.P. 144-145 bothrecrystallized from ethyl acetate.

Analysis.-Calcd. for C H N O S (Via): C, 68.07; H, 7.07; N, 7.56; S,8.66. Found: C, 67.84; H, 6.95; N, 7.38; S, 8.94.

Analysis.-Calcd. for C H N O S (VIb): C, 68.07; H, 7.07; N, 7.56; S,8.66. Found: C, 68.05; H, 7.09; N, 7.42; S, 8.77.

Refluxing 0.90 g. (0.0024 mole) of a mixture of epimeric thioamides with7.0 g. of Raney nickel in 100 ml. of dry dioxane for 48 hours,filtration, washing of the residual Raney nickel with 100 ml. ofdichloromethane, concentration and crystallization from ligroin (B.P.60- 90) gave 0.65 g. (0.0019 mole) of a mixture of epimeric amino esterswhich could be separated by chromatography over 40 g. of neutral aluminawith petroleum ether (B.P. 30-60) and benzene as eluants. The morerapidly eluted epimer showed a M.P. 149-150", pKa 6.9, infrared max.1735 cm. (ester) and the less rapidly eluted epimer a M.P. 144-145, pKa6.5, infrared max. 1725 cm." (ester). Both recrystallized from ligroin(B.P. 6090).

Analysis.-Calcd. for C H N O (V1111): C, H, 8.29. Found: C, 74.13; H,8.32.

Analysis.-Calcd. for C H N O (VIIb): C, 74.09; H, 8.29. Found: C, 74.20;H, 8.40.

Alternatively, the individual epimeric amines could be obtained byidentical Raney nickel treatment of the individual epimeric thiolactams.

D. Interconversion of epimeric amino esters A solution of 13.0 mg.(0.0038 111. mole) of either amino ester epimer and 24 mg. (0.0075 In.mole) of mercuric acetate in 6 ml. of acetic acid was heated at 59 for 4hours. After 1 hour most of the indole ultraviolet absorption at 265,280 and 290 mu had disappeared and the characteristic absorption of thedidehydro compound at 250 and 358 m had been generated. The rate ofoxidation of the chromatog-raphically more slowly eluted epimer wasfound to be about twice that of the first eluted epimer. Concentrationunder vacuum, addition of 10 ml. of absolute ethanol and 0.50 g. ofsodium borohydride, stirring for 15 hours at room temperature,acidification, addition of 50 ml. of water and excess sodium hydroxide,extraction with ether and concentration gave a mixture of the originalepimeric amino esters in about equal amounts.

E. dl-vincamine, epivincamine, isovincamine and epiisovincamine Asolution of 33 mg. (0.10 m. mole) of the more rapidly eluted amino esterin 10 ml. of anhydrous ether was treated with an excess of sodiumtriphenylmethane in ether. After 25 minutes 15 mg. (0.10 m. mole) ofp-nitroso-N,N-dimethyl-aniline in 10 ml. of dry dioxane was added andthe reaction mixture stirred at 25 for 6 hours. Then 5 ml. of water wasadded and after 15 minutes the reaction mixture poured into 50 ml. ofwater and extracted five times with 30 ml. portions of ether.Concentration under vacuum, acidification with excess 3% hydrochloricacid, addition of excess aqueous sodium hydroxide after 10 minutes andextraction with dichloromethane and concentration of the extracts gave amixture which was separated by thin layer chromatography on alumina with0.5% methanol in dichloromethane. The fastest moving fraction yielded1.2 mg. of dl-vincamine. Another isolated product showing analogous butsomewhat different spectral and chromatographic characteristics yieldedepivincamine. Similarly, oxidation of the other epimeric amino esterproduced isovincamine and epiisovincamine in analogous amounts, andreadily differentiated from vincamine and epivincamine by thin layerchromatography using the system described above.

Identification of the dl-vincamine was accomplished by comparisonthereof with a sample of pure natural vincamine whereby such samplesyielded identical t.1.c. retention times in multiple adsorption andsolvent systems and identical infrared solution spectra.

The invention thus enables the preparation of pharmacologically activevincamine, its stereoisomers and intermediates useful in the preparationthereof.

The preceding example is not to be construed as limiting the invention.It is evident to those skilled in the art that temperatures, solvents,reaction conditions and equivalent techniques may be used withoutdeparting from the spirit of the invention or the scope of the appendedclaims.

Iclaim:

1. A method for the synthesis of vincamine comprising the steps of (a)condensation of tryptamine with 4-ethyl-4-formyldimethyl pimelateyielding a lactam ester product;

(b) reaction of said lactam ester product with phosphorus pentasulfideyielding a thiolactam ester product;

(0) desulfurization of said thiolactam ester product yielding twoepimeric aminoesters;

(d) chromatographic separation of said aminoesters;

(e) oxidation of the more rapidly eluted aminoester and subsequent acidtreatment to yield vincamine; and

(f) isolation of vincamine from the product by chromatographicseparation.

References Cited Pailer et al., Monatash fur Chemie, vol. 85, pp. 1055-1059 (1949).

Mokry et al., Tetrahedron Letters #15, pp. 999-1000, (1963).

HENRY R. IILES, Primary Examiner.

R. T. BOND, Assistant Examiner.

US. Cl. X.R. 260293.2, 293.4, 294, 294.7, 295, 326.3, 999

